Chemoselective alkoxycarbonylation reagent having trifluoromethyl-
sulfonyl-4-trifluoromethylanilide as a leaving group†
Tomohisa Yasuhara, Yasuo Nagaoka and Kiyoshi Tomioka*
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606–8501,
Japan
Received (in Cambridge) 9th July 1999, Accepted 14th July 1999
N-Benzyloxy- and N-tert-butoxycarbonyltrifluoromethyl-
sulfonyl-4-trifluoromethylanilides were prepared and were
found to be chemoselective and shelf-storable alkoxy-
carbonylation reagents.
Selective alkoxycarbonylation of amines according to their
chemical types is an important synthetic operation. Selective
reagents have been developed by devising a leaving group such
as chloride,1 imidazolide,2 imide,3 oxime,4 enolate,5 and so on.6
Although some of the reagents are now commercially available,
continuing efforts have been made to develop an ideally select-
ive reagent.7 It is reasonably assumed that a reagent having a
bulky leaving group may satisfy such a requirement. However,
bulkiness retards the reaction as well. We designed a new alkoxy-
carbonylation reagent of amines employing trifluoromethyl-
sulfonyl-4-trifluoromethylanilide as a leaving group. Since the
trifluoromethylsulfonyl and 4-trifluoromethylphenyl groups
are powerful electron-withdrawing ones,8 the sulfonamide of
4-trifluoromethylaniline is expected to behave as a bulky and
excellent leaving group. Calculation of Z-anilide 1 (Scheme 1)
Fig. 1 Selective benzyloxy- and tert-butyloxycarbonylation.
TLC. A typical primary amine, 2-phenylethylamine, was con-
verted into the Z-derivative in 95% yield within 5 min by treat-
ing with 1.2 equiv. of 1 (Table 1). An α-branched primary
amine, 1-phenethylamine, was converted into the Z-derivative
in 99% yield in 15 min. It took 24 h for the conversion of tert-
butylamine into the Z-derivative in 88% yield. A secondary
amine, benzylmethylamine, was converted into the Z-derivative
in 99% yield in 5 min. Aniline was benzyloxycarbonylated in
97% yield in 3 h. N-Methylaniline, however, was slowly con-
verted to the Z-derivative in 89% yield in 24 h. These differences
in the reaction time apparently indicate the high chemoselectiv-
ity of 1, which distinguishes steric and electronic characters
of amines. Thus, primary amine-selective monobenzyloxy-
carbonylation of a diamine, N-(2-aminoethyl)benzylamine, was
realized by treating with 1.0 equiv. of 1 at 0 ЊC for 3 h in THF
to afford the mono-Z-derivative15 in 95% yield (Fig. 1). The
leaving group of 1, trifluoromethylsulfonyl-4-trifluoromethyl-
anilide, was recovered quantitatively for recycling simply by
extracting with aq. sodium bicarbonate. After washing, concen-
tration gave the benzyloxycarbonylated product, which was
purified by recrystallization or column chromatography.
Scheme 1
by MOPAC (PM3, precise mode) indicated that the 4-trifluoro-
methylphenyl group is placed almost perpendicular to the plane
The Z-anilide 1 was also a good benzyloxycarbonylation
reagent for α-amino acids. Treatment with 1.1 equiv. of 1 in a
1:1 mixture of aq. dioxane in the presence of 1.5 equiv. of
triethylamine at rt for 0.2–24 h gave Z-amino acids in high
yields without racemization as shown in Table 2.
of O᎐C–N.9 Therefore, sufficient steric bulkiness is provided
᎐
around the carbonyl group. We describe herein that 1 and Boc-
anilide 2 are chemoselective and rapid alkoxycarbonylation
reagents of amines.
Attempted benzyloxycarbonylation of N-trifluoromethylsulf-
onyl-4-trifluoromethylaniline10 under the standard acylation
conditions,11 ZCl and triethylamine–DMAP in chloroform at
rt for 12 h, however, gave an N-benzylation product in 84% yield
without formation of the expected Z-anilide 1.12 Fortunately,
this problem was solved by treating the sodium salt of sulf-
onylanilide with ZCl in THF at 0 ЊC for 24 h. After column
chromatography, 1 was obtained as shelf-storable needles of mp
105–107 ЊC in 76% yield together with N-benzylsulfonylanilide
in 24% yield.13 Boc-anilide 2 was also prepared under the same
conditions for 1 using (Boc)2O in 95% conversion yield as shelf-
storable needles of mp 65–67 ЊC.
Under the same conditions using 2, 2-phenylethyl, 1-phenyl-
ethyl, and benzylmethylamines were converted to the Boc-
derivatives in 99, 90, and 90% yields for 0.1, 1, and 1 h, respect-
ively (Table 1).16 Aniline and tert-butylamine were not con-
verted to the Boc-derivatives at rt for 24 h; instead they were
recovered unchanged. However, upon addition of 0.1 equiv. of
DMAP these amines were converted to the Boc-amines in high
yields. Proline and phenylalanine were converted into Boc-
amino acids in 97 and 59% yields for 24 h (Table 2). These
impressive differences in reactivity are attributable to the effi-
cient bulkiness around the carbonyl group of 2 by the tert-
butoxy and sulfonylanilide groups, indicating that reactivity of
2 is sensitive to the steric and electronic characters of the
amines. Chemoselective tert-butyloxycarbonylation was also
possible in the presence of cat. DMAP (Fig. 1).
Benzyloxycarbonylation of several types of amines with 1
was examined in THF at rt.14 The reaction was monitored by
In conclusion, the anilides 1 and 2 were shown to be chem-
oselective and shelf-storable crystalline alkoxycarbonylation
reagents. Since ZCl is an irritant, unstable liquid, and (Boc)2O is
a solid of low melting point, 1 and 2 are good alternatives.
We gratefully acknowledge financial support from Japan
† Experimental details for the preparation and reactions of 1 and 2 are
available as supplementary data. For direct electronic access see http://
www.rsc.org/suppdata/p1/1999/2233, otherwise available from BLDSC
(SUPPL. NO. 57604, pp. 2) or the RSC Library. See Instructions for
J. Chem. Soc., Perkin Trans. 1, 1999, 2233–2234
2233